Anti-hyperuricemia composition

ABSTRACT

Compositions useful in the treatment of gout and hyperuricemia and containing a substituted 1,2,4-triazole as the active ingredient are provided, the triazoles being substituted at the 5 position with a pyridyl radical and at the 3 position with a phenyl or a pyridyl radical. Methods of preparing these substituted triazoles are described. Certain of the compounds are novel.

This is a division of copending application Ser. No. 361,915, filed May21, 1973, now U.S. Pat. No. 3,892,762, which is in turn acontinuation-in-part of Ser. No. 75,784 filed Sept. 25, 1970, nowabandoned.

BACKGROUND OF THE INVENTION:

1. Field of the Invention

The invention relates to the use of certain 1,2,4-triazoles which aresubstituted in the 3 and 5 positions, and which may optionally besubstituted in the 1 position as antigout and anti-hyperuricemic agents.

2. Description of the Prior Art

The herein-described 3,5-di-substituted-1,2,4-triazoles have utility asanti-gout and anti-hyperuricemic agents.

Gout is a condition affecting humans and lower animals, which ischaracterized by perversion of the purine metabolism resulting inhyperuricemia, i.e. an excess of uric acid in the blood, attacks ofacute arithritis, and formation of chalky deposits in the cartilages ofthe joints. These deposits are made up chiefly of urates, or uric acid.

Uric acid serves no biochemical function in the body and is merely anend product of purine metabolism. It is well known in the art that thepurine bases adenine and guanine, which play key roles in a wide varietyof chemical processes, both give rise to uric acid in the body. Adenylicacid and guanylic acid are converted to the free purine bases bydestructive metabolic enzymes. A portion of the free purine bases isconverted to purine ribonucleotides and the remainder is degraded to thefree bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase,converts both xanthine and hypoxanthine to uric acid for excretion.

Although human purine biosynthesis can be inhibited at the stage offormyl glycinimide ribotide by the glutamine antagonists azaserine and6-diazo-5-oxo-1-norleucine, a high incidence of undesirable side effectsprecludes their being used clinically for this purpose. In recent years,substantial progress had been made in attempting to control theexcessive levels of uric acid in patients afflicted with gout throughthe use of pharmaceutical agents. Uric acid synthesis has beeneffectively blocked by the use of allopurinol, i.e.4-hydroxypyrazolo-[3,4-d]-pyrimidine, a compound which is a structuralisomer of hypoxanthine. Allopurinol acts as a specific inhibitor of theenzyme xanthine oxidase, which is responsible for the conversion of bothhypoxathine and xanthine to uric acid. As a direct result of theadministration of this compound to patients afflicted with gout, part ofthe uric acid which would normally end up in the urine is replaced bythe oxypurines, hypoxanthine and xanthine, thus greatly reducing thecontent of uric acid in serum and urine. Azathioprine has also been usedto inhibit excessive purine synthesis, and thus reduce the abnormallyhigh amounts of uric acid found in the serum and urine of afflictedpatients. Other compounds, such as acetylsalicylic acid,thiophenylpyrazolidine and phenylbutazone have been employed in thetreatment of gout. Many of the existing compounds used in the treatmentof gout, however, relieve the inflammation and other symptoms connectedtherewith but have no effect on the conditions which give rise to goutyarthritis or hyperuricemia. Thus, there is still a need for compoundswhich can be employed in the prophylactic treatment of gout as well asfor the treatment of other abnormal conditions associated withhyperuricemia.

SUMMARY OF THE INVENTION

According to this invention it has been found that compounds of theFormulas Ia and Ib ##SPC1##

where R₁ represents hydrogen, loweralkyl, lower alkanoyl, benzenesulfonyl, carbamoyl or loweralkyl carbamoyl, R₃ represents phenyl,loweralkylphenyl, pyridyl or lower alkyl pyridyl, and R₅ representspyridyl or loweralkyl pyridyl; are useful as anti-gout andanti-hyperuricemic agents in that they inhibit the action of xanthineoxidase and thus reduce the uric acid content of serum and urine. Alsouseful for the same purpose are the N-oxides and pharmaceuticallyacceptable non-toxic acid salts of such compounds, the N-oxides and thesalts being of the pyridine ring present in the molecule.

These compounds also posses useful hypotensive activity and some of thecompounds exhibit bronchodilating properties.

There are provided pharmaceutical compositions containing thesesubstances as anti-gout, anti-hyperuricemic and hypotensive agents, andthe method of treating gout, hyperuricemia and of lowering bloodpressure by administration of effective amounts of such compounds andcompositions containing them to a host requiring them.

Certain of these compounds are novel, for example, the N-oxides, thosewherein R₁ is other than hydrogen, and those where R₅ is other than4-pyridyl, and the invention contemplates providing these novelcompounds and methods of preparing them.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred compounds to be used in the compositions and methods ofthis invention as anti-gout, anti-hyperuricemic and hypotensive agentsare those of Formulas Ia and Ib above wherein R₁ is hydrogen, aloweralkyl radical and preferably one containing from 1-5 carbons,saturated or unsaturated, such as methyl, ethyl, butyl, amyl, propenylor propargyl, a lower-alkanoyl radical and preferably one of 2-6 carbonssuch as acetyl, propionyl, butyryl, benzenesulfonyl, a carbamoyl ordiloweralkylcarbamoyl radical where the loweralkyls are preferablymethyl, ethyl or propyl. In the most preferred aspect of the invention,R₁ is hydrogen.

R₃ represents a phenyl or alkylphenyl radical which may have from 1-3alkyl substituents which are preferably loweralkyl such as methyl,ethyl, or butyl. It also represents pyridyl or loweralkyl pyridyl, thelatter containing from 1 to 3 loweralkyl groups which may be the same ordifferent and preferably are methyl, ethyl or propyl. The pyridyl oralkylpyridyl substituent may be any one of the three possible isomers.In the most preferred aspects of the invention, R₃ is phenyl or4-pyridyl.

R₅ can be pyridyl or loweralkyl pyridyl as described for the R₃substituent. The preferred compounds are those wherein R₅ is 4-pyridyl.

Included within the scope of the invention are the pharmaceuticallyacceptable salts of these 1,2,4-triazoles. They include the alkali andalkaline earth metal salts such as the sodium, potassium and calcium.Also included are the acid addition salts and quaternary salts of thepyridyl nitrogen, examples being the methiodides, ethiodides,hydrochlorides, sulfates, tartrates, oxalates and the like. N-oxides ofthe pyridyl substituents are also within the scope of the invention.

As previously stated, the foregoing compounds have the property ofreducing the concentration of uric acid in blood and urine, and also ofreducing blood pressure. These therapeutically active compounds areadministered to mammals requiring such treatment admixed with orintimately dispersed in a pharmaceutically acceptable carrier,preferably in the form of a solid, orally administrable, unit dosageform such as tablets, or capsules, or as solutions or suspensions of thetype represented by syrups and elixers. The amount of active ingredientin the pharmaceutical composition may be varied within reasonable limitsdepending upon such factors as pharmaceutical elegance and the amount ofdrug desired at each administration. It is convenient to employ solidunit dosage formulations containing from about 25-500 milligrams ofactive ingredient, and liquid preparations containing from about 5-40%by weight of triazole.

These pharmaceutical compositions may be made be any of the knownpharmaceutical methods. For example, for tablets the triazoles arecompounded with an inert pharmaceutical carrier which may contain asuitable binder such as, for example, gums, starches, and sugars. Theymay also be incorporated into a gelatin capsule with or without adiluent, or formulated into elixirs, syrups or suspensions which havethe advantage of being susceptible to manipulations in flavor by theaddition of standard natural or synthetic flavoring materials. Thecompound is generally administered in compositions which are soproportioned as to afford a dosage of about 30 mg. to 1.5 gm. per day asthe effective amount. The preferred oral dosage level is about 100-800mg. per day.

The following examples serve to illustrate typical tablet, capsule, andelixir formulations containing the therapeutically active triazoles ofthis invention:

    FORMULATION I: COMPRESSED TABLET COMPRISING                                   0.5 GM. OF ACTIVE INGREDIENT                                                  INGREDIENT                AMOUNT-MG.                                          ______________________________________                                        3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole                                                             500.0                                                Starch paste- 121/2%, 100 cc. allow.                                                                   12.5                                                                          512.5                                                Starch, U.S.P. Corn      25.0                                                 Magnesium stearate       5.5                                                                           543.0                                                ______________________________________                                    

The 3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole is granulated with thestarch paste and while moist passed through a No. 14 screen, dried at45° C. for 20 hours, and then passed 3 times through a No. 14 screen.The starch is then passed through a No. 90 bolting cloth onto thegranulation, and all ingredients are blended thoroughly. The magnesiumstearate is passed through a No. 90 bolting cloth onto the granulation,and these ingredients are blended, after which the granulation iscompressed into tablets using 14/32" flat, bevelled, scored punch havinga thickness of 0.025± 0.005" yielding 1,000 tablets each weighing 0.543grams.

A similar tablet containing 3,5-di-(4-pyridyl)-1,2,4-triazole isprepared by following the above procedure and using thedi-(4-pyridyl)-triazole as active ingredient.

    ______________________________________                                        FORMULATION II: ENCAPSULATION - FOR 350 MG. CAPSULE                           INGREDIENT               AMOUNT-MG.                                           ______________________________________                                        3-phenyl-5-(4-pyridyl)-1,2,4-triazole                                                                  250                                                  Lactose                  93                                                   Talc                     7                                                    ______________________________________                                    

The lactose, talc and the 3-phenyl-5-(4-pyridyl)-1,2,4-triazole areblended in suitable blending equipment, and encapsulated into a No. 2capsule at a target weight of 350 mg.

    ______________________________________                                        FORMULATION III: LIQUID SUSPENSION - FORMULA                                  INGREDIENT               AMOUNT-g./1.                                         ______________________________________                                        Veegum H.V.              3.0                                                  Water                    150.0                                                Methyl paraben           1.0                                                  1-methyl-3,5-di(4-pyridyl)-1,2,4-triazole                                                              50.0                                                 Kaolin                   10.0                                                 Flavor                   1.0                                                  Glycerin, 9.5 to 1 liter                                                      ______________________________________                                    

Suspend Veegum in water with vigorous agitation, add methyl, paraben andallow to stand overnight to ensure complete hydration of Veegum. Inseparate vessel suspend 1-methyl-3,5-di-(4-pyridyl)-1,2,4-triazole inabout 750 cc. of glycerin. Add kaolin and stir until homogenous. Slowlyadd aqueous dispersion of Veegum and methyl paraben. Add flavor andcontinue agitation for 1 hour to ensure homogeneity. Q.S. with remainingglycerin to 1:1. Stir until homogeneous. 1 Teaspoonful contains 250 mg.of 1-methyl-3,5-di-(4-pyridyl)-1,2,4-triazole.

Representative compounds which are part of the present invention whichmay be formulated as described above are:

3,5-di(2-pyridyl)-1,2,4-triazole,

5-(4-pyridyl)-3-(2-methyl-4-pyridyl)-1,2,4-triazole,

3,5-di(2-methyl-4-pyridyl)-1,2,4-triazole,

5-(4-pyridyl)-3-(2,6-dimethyl-4-pyridyl)-1,2,4-triazole,

3,5-di(2,6-dimethyl-4-pyridyl)-1,2,4-triazole,

1-butyryl-3,5-di(4-pyridyl)-1,2,4-triazole,

1-acetyl-3,5-di(4-pyridyl)-1,2,4-triazole,

1-ethyl-3,5-di(2-pyridyl)-1,2,4-triazole,

1-carbamoyl-3,5-di(2-pyridyl)-1,2,4-triazole,

3,5-di(4-pyridyl)-1,2,4-triazole,

3-phenyl-5-(4-pyridyl-N-oxide)-1,2,4-triazole,

3,5-di(4-pyridyl)-1,2,4-triazole hydrochloride, and

3-(2,4,6-trimethylphenyl)-5-(2-methyl-5-ethyl-4-pyridyl)-1,2,4-triazolesulfate.

The compounds of Formulas Ia and Ib can be prepared by the series ofreactions set forth in the following flow diagram: ##SPC2##

wherein R₁ is hydrogen or alkyl and R₃ and R₅ are as defined above, andW is a lower alkyl group containing 1-5 carbons.

As can be seen from the above reaction scheme, a substituted hydrazidecompound such as, for example, an acid hydrazide of formula IIa or IIbis reacted with an imino ester of formula IIIa or IIIb in a suitablesolvent. Either low boiling solvents such as methanol, ethanol, ornitromethane, or high boiling solvents such as decalin, xylene ordimethylsulfoxide may be employed. When low boiling solvents are used,the product of the reaction is usually the intermediate acylamidrazoneIVa or IVb. A reaction time of 3-20 hours at temperatures from roomtemperature to the reflux temperature of the solvent is employed.Depending upon the nature of the R₁ substituent, either the finalcyclized product is obtained or the intermediate acylamidrazone. In thecase where the intermediate acylamidrazone is obtained, the intermediatemay be heated without solvent at about 100°-300°C. for from about 15minutes to several hours, or it may be heated in a high boiling solventat a temperature from about 100°-200°C. for about 1-20 hours.

The final cyclized product is isolated and purified by techniques knownin the art. When high boiling solvents are employed, the reaction isconveniently carried out at or near the reflux temperature of thesolvent. The preferred temperature range is between 100°-200°C. Thereaction time is dependent upon the particular temperature rangeemployed. The reaction is carried out without isolation of theintermediate and the final cyclized product is isolated and purified bytechniques known in the art. For example, the product may becrystallized from a suitable solvent, such as methanol or ethanol. Ascan be seen from the above reaction diagram, where R₁ is alkyl, theselection of the particular hydrazide compound and the particular iminoester will depend upon whether the alkyl substituent is desired adjacentto the R₃ or R₅ substituent.

Compounds having a substituent in the 1-position can also be prepared byreacting the 3,5-di-substituted triazole with an appropriate alkylating,acylating or carbamoylating agent. Where R₃ and R₅ are both differentsubstituents, a mixture of compounds is obtained, i.e., the R₁substituent may be attached to either one of the adjacent nitrogens inthe triazole ring. For example, where the R₁ substituent is a loweralkanoyl group such as an acetyl or butyryl group, the triazole isreacted with a lower alkyl anhydride such as, for example, aceticanhydride or butyric anhydride. Where the R₁ substituent is an alkylgroup, alkylation is achieved by reacting the sodium salt of thetriazole with an alkylating agent such as, for example, dimethylsulfate.Alkylation of the 1,2,4-triazoles generally occurs in the 1-position.Where the alkyl group is a methyl group, methylation can be achieved byreacting the triazole with diazomethane in a suitable solvent, such asdiethylether. The 1-carbamoyl compounds can be synthesized by reactingthe sodium salt of the triazole with carbamoyl halide or di-lower alkylcarbamoyl halide in an inert solvent such as tetrahydrofuran.

The following examples are given for the purpose of illustration and notby way of limitation.

EXAMPLE 1 5-(4-PYRIDYL)-3-(2-METHYL-4-PYRIDYL)-1,2,4-TRIAZOLE

Sodium (0.4 grams) is added to 4-cyanopyridine (8.3 grams, 0.08 mole) inmethanol, and the solution is allowed to stand 30 minutes at roomtemperature. A suspension of 2-methylisonicotinic acid hydrazide (0.07mole) in methanol (160 ml.) is added, and the resulting solution isheated at reflux for 30 minutes. After cooling, the intermediateacylamidrazone is collected by filtration. The acyclic intermediate isthen heated at 260°C. for 15 minutes, after which the reaction is cooledto room temperature. Upon recrystallization from acetonitrile-water,5-(4-pyridyl)-3-(2-methyl-4-pyridyl)-1,2,4-triazole is obtained, m.p.245°-248°C.

EXAMPLES 2 - 9

The following compounds are prepared by the reaction procedure describedin Example 1.

    __________________________________________________________________________    EXAMPLES 2-9                                                                  EXAMPLE                                                                             HYDRAZIDE   NITRILE       COMPOUND        MELTING                       __________________________________________________________________________                                                    POINT                         2     2-methylisonicotinic                                                                      2-methyl-4-cyanopyridine                                                                    3,5-bis(2-methyl-4-pyridyl)-                                                                  229-231°C.                   acid hydrazide            1,2,4-triazole                                3     isonicotinic acid                                                                         2,6-dimethyl-4-cyano-                                                                       5-(4-pyridyl)-3-(2,6-di-                                                                      292-293°C.                   hydrazide   pyridine      methyl-4-pyridyl)-1,2,4-                                                      triazole                                      4     2,6-dimethylisonico-                                                                      2,6-dimethyl-4-cyano-                                                                       3,5-bis(2,6-dimethyl-4-                                                                       313-314°C.                   tinic acid hydrazide                                                                      pyridine      pyridyl)-1,2,4-triazole                       5     nicotinic acid                                                                            2-cyanopyridine                                                                             3-(2-pyridyl)-5-(3-pyridyl)-                                                                  246.5-248°C.                 hydrazide                 1,2,4-triazole                                6     isonicotinic acid                                                                         2-cyanopyridine                                                                             3-(2-pyridyl)-5-(4-pyridyl)-                                                                  260-261°C.                   hydrazide                 1,2,4-triazole                                7     nicotinic acid                                                                            3-cyanopyridine                                                                             3,5-di(3-pyridyl)-1,2,4-                                                                      223-225°C.                   hydrazide                 triazole                                      8     p-toluic acid                                                                             4-cyanopyridine                                                                             3-(p-tolyl)-5-(4-pyridyl)-                                                                    226-228°C.                                                             - hydrazide  1,2,4-triazol                                                    e                             9     isonicotinic acid                                                                         4-cyanopyridine-N-oxide                                                                     5-(4-pyridyl)-3-(4-pyridyl-                                                                   332-334.5°C.                 hydrazide                 1-oxide)-1,2,4-triazole                       __________________________________________________________________________

EXAMPLE 10 1-BUTYRYL-3,5-DI(4-PYRIDYL)-1,2,4-TRIAZOLE

3,5-DI(4-pyridyl)-1,2,4-triazole (0.5 grams) is added to butyricanhydride (10 ml.), and the reaction mixture is heated at steam bathtemperatures for 20 hours. The resulting solution is concentrated untila solid separates out of solution, and the solid is collected byfiltration. Upon recrystallization from hexane,1-butyryl-3,5-di(4-pyridyl)-1,2,4-triazole is obtained, m.p. 116°-118°C.

When in the above procedure acetic anhydride is employed in place ofbutyric anhydride, 1-acetyl-3,5-di (4-pyridyl)-1,2,4-triazole isobtained, m.p. 155.5°-158°C.

When in the above procedure propionic anhydride is employed in place ofbutyric anhydride, 1-propionyl-3,5-bis-(4-pyridyl)-1,2,4-triazole isobtained.

EXAMPLE 11 1-METHYL-3,5-DI(4-PYRIDYL)-1,2,4-TRIAZOLE

To a solution of 4-cyanopyridine (4.1 grams, 0.04 mole) in methanol (60ml.) is added sodium (0.2 grams). The resulting solution is allowed tostand at room temperature for 1/2 hour and is then added to a solutionof N-methylisonicotinic acid hydrazide (6 grams, 0.04 mole) in methanol(80 ml.). The solution is refluxed for 3 hours and is then concentrateduntil a solid separates out of solution. The solid is collected byfiltration and, upon recrystallization from ethanol,1-methyl-3,5-di(4-pyridyl)-1,2,4-triazole is obtained, m.p. 168°-170°C.

EXAMPLE 12 1-METHYL-3-(4-PYRIDYL)-5-(4-PYRIDYL-1-OXIDE)-1,2,4-TRIAZOLE

To a solution of 4-cyanopyridine-N-oxide (4.1 grams, 0.04 mole) inmethanol (60 ml.) is added sodium (0.2 grams). The resulting solution isallowed to stand at room temperature for 1/2 hours and is then added toa solution of 1-isonicotinoyl-2-methylhydrazine (6 grams, 0.04 mole) inmethanol (80 ml.). The solution is refluxed for 3 hours and is thenconcentrated until a solid separates out of solution. The solid iscollected by filtration, and, upon recrystallization from ethanol,1-methyl-2-(4-pyridyl)-5-(4-pyridyl-1-oxide)-1,2,4-triazole is obtained,m.p. 219°-221°C.

EXAMPLE 13 1-BENZENSULFONYL-3,5-DI(4-PYRIDYL)-1,2,4-TRIAZOLE

To 1.06 g. (0.005 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 100 ml.of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.21 g.,0.005 mole). The reaction mixture is heated at reflux for 1/2 hour,cooled and a solution of benzenesulfonyl chloride (0.88 g., 0.005 mole)is added. The reaction mixture is heated at reflux for 1/2 hour, cooled,filtered and concentrated to a solid. After recrystallization fromacetonitrile 0.4 g. of1-benzenesulfonyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at210°-212°C. is obtained.

EXAMPLE 14 1-DIMETHYLCARBAMOYL-3,5-DI(4-PYRIDYL)-1,2,4-TRIAZOLE

To 2.13 g. (0.01 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 200 ml. oftetrahydrofuran is added 57% sodium hydride in mineral oil (0.42 g.,0.01 moles). The reaction mixture is heated at reflux for 1 hour, cooledand a solution of dimethylcarbamoyl chloride (1g., 0.01 mole) in 10 ml.of tetrahydrofuran is added dropwise. The reaction mixture is heated atreflux for 4 hours, cooled, filtered and concentrated to an oil whichsolidifies. After recrystallization from benzene 1.2 g. of1-dimethylcarbamoyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at140°-141.5°C. is obtained.

EXAMPLE 15 1-METHYL-3-(p-CHLOROPHENYL)-5-(3-PYRIDYL)-1,2,4-TRIAZOLE

To 3-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.).The solution is allowed to stand 0.5 hours at ambient temperature and isthen added to a solution of 1-methyl-2-(p-chlorobenzoyl)hydrazine (3.6g.) in methanol (40 ml.). The reaction mixture is heated at reflux for 5hours and is then concentrated to an oil which solidifies. Afterrecrystallization from isopropanol, yielding 0.2 g of1-methyl-3-(p-chlorophenyl)-5-(3-pyridyl)-1,2,4-triazole, m.p.157°-158°C. is obtained.

EXAMPLE 16 1-METHYL-3-(p-CHLOROPHENYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

When 4-cyanopyridine is used in place of 3-cyanopyridine in the processdescribed in Example 15,1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole is obtainedwhich melts at 191°C.

EXAMPLE 17 1-METHYL-3(3-PYRIDYL)-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

To 4-cyanopyridine (2g.) in methanol (30 ml.) is added sodium (0.1 g.).The solution is allowed to stand 0.5 hours at ambient temperature and isthen added to a solution of 1-methyl-2-nicotinoyl-hydrazine (3 g.) inmethanol (30 ml.). The reaction mixture is heated 5 hours at reflux andis concentrated to an oil which solidifies. After chromatography onsilica gel and recrystallization from acetonitrile 0.8 g. of1-methyl-3-(3-pyridyl)-5-(4-pyridyl)-1,2,4-triazole melting 132°-133° Cis obtained.

EXAMPLE 18 1-METHYL-3,5-BIS(3-PYRIDYL)-1,2,4-TRIAZOLE

When 3-cyanopyridine is used in place of 4-cyanopyridine in the processof Example 17, 1-methyl-3,5-bis(-3-pyridyl)-1,2,4-triazole is obtainedmelting at 148°-149° C.

EXAMPLE 19 1METHYL-3-PHENYL-5-(3-PYRIDYL)-1,2,4-TRIAZOLE

To 3-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.).The solution is allowed to stand 0.5 hours at ambient temperature and isthen added to a solution of 1-methyl-2-benzoylhydrazine (3 g.) inmethanol (40 ml.). The solution is heated 5 hours at reflux and is thenconcentrated to an oil which solidifies. After chromatography on silicagel and recrystallization from a mixture of acetonitrile and water,there is obtained 200 mg. of1-methyl-3-phenyl-5-(3-pyridyl)-1,2,4-triazole, m.p. 97°-98° C.

EXAMPLE 20 1-METHYL-3-PHENYL-5-(2-PYRIDYL)-1,2,4-TRIAZOLE

When 2-cyanopyridine is used in place of 3-cyanopyridine in the processof Example 19, 1-methyl-3-phenyl-5-(2-pyridyl)-1,2,4-triazole isobtained, m.p. 105.5°-107.5° C.

EXAMPLE 21 1-METHYL-3-PHENYL-5-(4-PYRIDYL)-1,2,4-TRIAZOLE

When 4-cyanopyridine is used in place of 3-cyanopyridine in the processof Example 19, 1-methyl-3-phenyl-5-(4-pyridyl)-1,2,4-triazole isobtained, m.p. 132°-134° C.

EXAMPLE 22 1-METHYL-3-(4-PYRIDYL)-5-(2-PYRIDYL)-1,2,4-TRIAZOLE

To 2-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.).The solution is allowed to stand 0.5 hours at ambient temperature and isthen added to a solution of 1-methyl-2-isonicotinoylhydrazine (3 g.) inmethanol (50 ml.). The solution is heated at reflux 4 hours andconcentrated to a gum. After chromatography on silica gel andrecrystallization from acetonitrile-water 450 mg. of1-methyl-3-(4-pyridyl)-5-(2-pyridyl)-1,2,4-triazole are obtained,melting at 145°-146° C.

EXAMPLE 231-METHYL-3(4-PYRIDYL)-5-(2,6-DIMETHYL-4-PYRIDYL)-1,2,4-TRIAZOLE

When 2,6-dimethyl-4-cyanopyridine is used in place of 2-cyanopyridine inthe process of Example 22,1-methyl-3(4-pyridyl)-5-(2,6-dimethyl-4-pyridyl)-1,2,4-triazole isobtained, m.p. 176°-178° C.

EXAMPLE 24 1-METHYL-3(4-PYRIDYL)-5-(3-PYRIDYL)-1,2,4-TRIAZOLE

When 3-cyanopyridine is used in place of 2-cyanopyridine in the processof Example 22, 1-methyl-3(4-pyridyl)-5-(3-pyridyl)-1,2,4-triazole isobtained which melts 143°-144.5° C.

EXAMPLE 25 1-n-PROPYL-3,5-BIS(4-PYRIDYL)-1,2,4-TRIAZOLE

To 3,5-bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mole) in drytetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1g. 0.024 mole) and the mixture is heated 45 minutes at reflux. Thesuspension is concentrated to a solid, N,N-dimethylformamide (70 ml.)and n-propyl iodide (0.022 mole) are added. The mixture is stirred 0.5hour at ambient temperature followed by heating on the steam bath for 4hours. The solution is concentrated to a gum, water is added and thematerial solidifies. Following recrystallization from methylcyclohexanethere is obtained 1-n-propyl-3,5-bis(4-pyridyl)-1,2,4-triazole, m.p.88°-89° C.

EXAMPLES 26 - 30

Following substantially the same procedure described in Example 25 butreplacing the n-propyl iodide by an equimolecular quantity of thealkylating agent identified in column 2 of the following table, the 1-R₁-3,5-bis(4-pyridyl)-1,2,4-triazole compound having the R₁ substituentidentified in column 3 is obtained.

    ______________________________________                                                  Alkylating             Melting                                      Example No.                                                                             Agent         R.sub.1  Point °C                              ______________________________________                                        26        Br--CH.sub.2 C.tbd.CH                                                                     --CH.sub.2 C.tbd.CH                                                                      175.5-176.5                                  27        Br--CH.sub.2 CH=CH.sub.2                                                                  --CH.sub.2 CH=CH.sub.2                                                                   127-128.5                                    28        I--CH.sub.2 CH.sub.3                                                                      --CH.sub.2 CH.sub.3                                                                      139-140                                      29        I--CH(CH.sub.3).sub.2                                                                     --CH(CH.sub.3).sub.2                                                                     123.5-125.5                                  30        I--(CH.sub.2).sub.3 CH.sub.3                                                              --(CH.sub.2).sub.3 CH.sub.3                                                              88.5-89.5                                    ______________________________________                                    

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

What is claimed is:
 1. A composition in unit dosage form for thetreatment of hyperuricemia which comprises from about 25 mg. - 1.5 g. ofa compound of the formula: ##SPC3##or a non-toxic pharmacologicallyacceptable salt thereof, intimately dispersed in a pharmaceuticallyacceptable carrier, wherein R₁ is hydrogen, lower alkyl, lower alkanoyl,carbamoxy, di-lower alkylcarbamoyl or benzene sulfonyl; R₃ is phenyl,lower alkylphenyl, tri-lower alkylphenyl, pryidyl, mono-loweralkylpyridyl or di-lower alkylpyridyl; and R₅ is pyridyl, mono-loweralkylpyridyl or di-lower alkylpyridyl; including the mono N-oxides ofthose products wherein R₃ and R₅ are both pyridyl.
 2. The composition ofclaim 1 wherein R₁ is hydrogen and R₅ is 4-pyridyl.
 3. The compositionof claim 1 wherein the active ingredient is3,5-di(4-pyridyl)-1,2,4-triazole.
 4. The composition of claim 1 whereinthe active ingredient is 1-isopyropyl-3,5-di(4-pyridyl)-1,2,4-triazole.5. The composition of claim 1 which is in a unit dosage form containingabout 25 to 500 mg. of active ingredient.
 6. The method of treatinghyperuricemia which comprises administering to a patient suffering fromgout an effective amount of a compound of the formula: ##SPC4##or anon-toxic pharmacologically acceptable salt thereof, wherein R₁ ishydrogen, lower alkyl, lower alkanoyl, carbamoyl, di-loweralkylcarbamoyl or benzenesulfonyl; R₃ is phenyl, lower alkylphenyl,tri-lower alkylphenyl, pyridyl, mono-lower alkylpyridyl or di-lowerakylpyridyl; and R₅ is pyridyl, mono-lower alkylpyridyl or di-loweralkylpyridyl; including the mono N-oxides of those products wherein R₃and R₅ are both pyridyl.
 7. The method of claim 6 wherein said compoundis administered at a daily dosage of from about 30 mg. to 1.5 gm.
 8. Themethod of claim 7 wherein the compound administered is3,5-di(4-pyridyl)-1,2,4-triazole.